Liu Shujie, Jiang Anfeng, Tang Faqing, Duan Minghao, Li Bin
Department of Oncology, Xiangya Hospital, Central South University, Changsha , Hunan, 410008, People's Republic of China.
Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.
Mol Cancer. 2025 May 24;24(1):150. doi: 10.1186/s12943-025-02323-9.
Cancer remains a significant global health burden due to its high morbidity and mortality. Oncogene-targeted therapy and immunotherapy have markedly improved the 5-year survival rate in the patients with advanced or metastatic tumors compared to outcomes in the era of chemotherapy/radiation. Nevertheless, the majority of patients remain incurable. Initial therapies eliminate the bulk of tumor cells, yet residual populations termed drug-tolerant persister cells (DTPs) survive, regenerate tumor and even drive distant metastases. Notably, DTPs frequently render tumor cross-resistance, a detrimental phenomenon observed in the patients with suboptimal responses to subsequent therapies. Analogous to species evolution, DTPs emerge as adaptative products at the cellular level, instigated by integrated intracellular stress responses to therapeutic pressures. These cells exhibit profound heterogeneity and adaptability shaped by the intricate feedforward loops among tumor cells, surrounding microenvironments and host ecology, which vary across tumor types and therapeutic regimens. In this review, we revisit the concept of DTPs, with a focus on their generation process upon targeted therapy or immunotherapy. We dissect the critical phenotypes and molecule mechanisms underlying DTPs to therapy from multiple aspects, including intracellular events, intercellular crosstalk and the distant ecologic pre-metastatic niches. We further spotlight therapeutic strategies to target DTP vulnerabilities, including synthetic lethality approaches, adaptive dosing regimens informed by mathematical modeling, and immune-mediated eradication. Additionally, we highlight synergistic interventions such as lifestyle modifications (e.g., exercise, stress reduction) to suppress pro-tumorigenic inflammation. By integrating mechanistic insights with translational perspectives, this work bridges the gap between DTP biology and clinical strategies, aiming for optimal efficacy and preventing relapse.
由于其高发病率和死亡率，癌症仍然是一个重大的全球健康负担。与化疗/放疗时代的结果相比，靶向癌基因疗法和免疫疗法显著提高了晚期或转移性肿瘤患者的5年生存率。然而，大多数患者仍然无法治愈。初始治疗消除了大部分肿瘤细胞，但称为耐药性持久细胞（DTPs）的残余细胞群存活下来，使肿瘤再生，甚至导致远处转移。值得注意的是，DTPs经常导致肿瘤交叉耐药，这是在对后续治疗反应欠佳的患者中观察到的一种有害现象。类似于物种进化，DTPs作为细胞水平的适应性产物出现，由对治疗压力的综合细胞内应激反应所激发。这些细胞表现出由肿瘤细胞、周围微环境和宿主生态之间复杂的前馈环所塑造的深刻异质性和适应性，这些在不同肿瘤类型和治疗方案中各不相同。在本综述中，我们重新审视了DTPs的概念，重点关注它们在靶向治疗或免疫治疗后的产生过程。我们从多个方面剖析了DTPs对治疗产生抗性的关键表型和分子机制，包括细胞内事件、细胞间串扰和远处的生态转移前微环境。我们进一步强调了针对DTPs脆弱性的治疗策略，包括合成致死方法、基于数学模型的适应性给药方案以及免疫介导的根除。此外，我们强调了协同干预措施，如生活方式的改变（如运动、减轻压力）以抑制促肿瘤炎症。通过将机制性见解与转化观点相结合，这项工作弥合了DTP生物学与临床策略之间的差距，旨在实现最佳疗效并预防复发。
